EPITHELIAL-MESENCHYMAL TRANSITION AND CROSS-TALK IN THE DEVELOPMENT OF LIVER FIBROSIS IN CONGENITAL FIBROCYSTIN DEFECTS (CONGENITAL HEPATIC FIBROSIS)

Mutations of the PKHD1 gene are responsible for severe liver diseases including Congenital Hepatic Fibrosis (CHF) and Caroli Disease (CD), characterized by cystic bile ducts with exuberant liver fibrosis, ultimately leading to portal hypertension, a severe complication also seen in advanced liver cirrhosis. The PKHD1 gene encodes for fibrocystin, a protein located in the bile duct cells and regulating the interactions with the matrix upon which they reside. In mice, inactivation of the corresponding gene results in a liver disease mimicking CHF/CD. Among other mechanisms, liver fibrosis could be the consequence of a biological process, relevant during embryonic development, called epithelial-mesenchymal transition (EMT), during which epithelial cells change their identity and become mesenchymal cells, the cells responsible for the generation of fibrotic tissue. EMT has been described in kidney and lung diseases, but not yet in genetic liver diseases. In this project, we will test the hypothesis that fibrocystin deficiency causes liver fibrosis promoting a process of EMT in the cystic epithelium. In our preliminary studies in both human and mice with defective fibrocystin, we have in fact observed that bile duct cells showed features consistent with EMT. Using a mouse model with a mutation in the Pkhd1 gene, we will study if fibrocystin defective bile duct cells are functionally engaged in EMT thereby being motile and able to produce fibrotic tissue proteins. Then, we will study if two peculiar intracellular signalling mechanisms (Wnt and Hedgehog), modulate EMT in mutated biliary cells. Finally, we will study the role of a receptor mediating activation of important molecules promoting EMT (TGF-b), called avb6 integrin and the effects of its pharmacological inhibition in vivo.